HIV/AIDS is a global pandemic with nearly 33 million individuals living with HIV infection worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV infection in developing countries, to determine the viral kinetics associated with sexual transmission, and to characterize the molecular strains of HIV internationally for infectiousness and progression of disease. We previously reported the results of a randomized clinical trial of circumcision to prevent HIV acquisition among 4,996 men in Uganda. The estimated efficacy of circumcision was 51% after 2 years but has risen to nearly 68% four years later. Circumcision also afforded a decrease in acquisition of high-risk- human papillomavirus (HR-HPV) in both HIV negative circumcised men as well as the female partners of circumcised men. HR-HPV incidence was 19.7/100py in the circumcised men and 29.4/100py in the control arm (p = 0.006). The incidence of multiple of HR-HPV infections was also reduced to 6.7/100py in the circumcised men and 14.8/100py in the control arm. HR-HPV incidence was lower in the circumcised men for all genotypes and demographic/behavioral subgroups. We also assessed the efficacy of circumcision to reduce HR-HPV in female partners. At two years of follow-up female HR-HPV prevalence was 27.8% in the intervention and 38.7% in the control arm (p=0.001). HR-HPV incidence was 20.7% in the intervention arm and 26.9% in the control arm wives (p=0.008). In summary male circumcision reduces acquisition of HIV, HSV and HPV infections in men, and reduces genital ulcer disease, HR-HPV, trichomoniasis, and bacterial vaginosis in their female partners. Since male circumcision reduces HIV, HPV and HSV-2 acquisition, we examined the cellular basis for these associations and estimated the immunologic cellular densities in foreskin tissues of men who were circumcised in the trial. CD1A+ dendritic cell densities did not vary by HIV or HSV-2 serologic status. When compared to HIV-/HSV-2- men, CD4+ T-cell densities in the foreskin tissue were similar in the HIV+/HSV-2+ group, significantly decreased in the HIV+/HSV-2 - group and increased in the HIV-/HSV-2+ group. CD8+ densities were higher in the HIV+/HSV-2+ infected group compared to the HIV-/HSV-2- group and the HIV+/HSV-2- group and the HIV-/HSV-2+ group (p <0.005). The increased CD4+ cellular density in the HIV-/HSV-2+ men may help explain why HSV-2 infected men are at increased risk for HIV acquisition. The absence of this increase in the HIV+/HSV-2+ group is likely in part due to the progressive loss of CD4+ in HIV infection. Conversely, co-infection with HIV and HSV-2 appear to synergistically increase the CD8+ T-cell densities and may partially explain the failure of acyclovir in decreasing sexual transmission of HIV in dually infected individuals. HIV superinfection has been described in a number of populations but its frequency and its clinical relevance remains unknown. We designed and tested a next generation sequencing protocol to identify HIV superinfection by targeting two regions of the HIV viral genome, p24 and gp41. The method was validated by mixing control samples infected with HIV subtypes A or D at different ratios to determine the inter- and intra-subtype sensitivity. This amplicon-based protocol was able to consistently identify distinct inter-subtype strains at ratios of 1%, and intra-subtype variants at 5%. Using stored samples from the Rakai Community Cohort Study (RCCS) in Uganda, eleven individuals who were HIV-seroconcordant but virally unlinked from their spouses were then tested with this method to detect superinfection between 2002-2005. Two female cases of HIV inter-subtype superinfection (18.2%) were identified. Our results indicate that NGS can be used for detection of HIV superinfection within large cohorts, which could assist in determining the incidence and the epidemiologic, virologic, and immunological correlates of this phenomenon. The significance of these studies is that they provide important epidemiologic, clinical, virologic and immunologic knowledge of HIV infection in developing countries, which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.